Human Prostacyclin Synthase Gene and Hypertension

There is a repeat polymorphism in the promoter region of the human prostacyclin synthase (PGIS) gene.  Certain manifestations of this polymorphism have now been shown to have significantly less promoter activity in cultured human umbilical vein endothelial cells.  Furthermore, persons with these alleles had a significantly higher likelihood of having elevated systolic pressure and pulse pressure, based on an epidemiological study conducted in Japan.

This research, reported in the November 30, 1999 issue of Circulation, adds weight to the argument that a prostacyclin synthase dysfunction underlies hypertension.  The lead scientist for the discovery, Dr. Naoharu Iwai, of the National Cardiovascular Center in Osaka Japan, observed that:

“Prostacyclin is a strong vasodilator that inhibits the growth of vascular smooth muscle cells and is also the most potent endogenous inhibitor of platelet aggregation. … In the present study, we identified a repeat polymorphism in the promoter region of the human prostacyclin synthase gene that is associated with promoter activity.  We then conducted an association study between this polymorphism and blood pressure in a population-based sample (the Suita Study) consisting of 4971 participants.  Our results indicate that the SS (R3R3 + R3R4 + R4R4) genotype, which is associated with lower transcriptional activity, is associated with higher pulse pressure in the overall population, especially among females, and with a higher systolic blood pressure in relatively older participants.  Because this repeat polymorphism affects systolic and pulse blood pressure, but not diastolic blood pressure, it may mainly affect the stiffness of conduit vessels.  The stiffness of conduit vessels seems to be determined by various factors, especially the content of the extracellular matrix, including collagen and elastin.  Prostacyclin synthase is abundantly expressed in vascular endothelial and smooth muscle cells, and prostacyclin has been shown to inhibit collagen expression.”

Dr. Iwai’s findings are directly relevant to pulmonary hypertension because the pulmonary arterioles are resistance vessels.  Excess stiffness in these vessels, due to an inadequate supply of prostacyclin (which in turn would result from depressed promoter activity of the prostacyclin synthase), is a hallmark characteristic of pulmonary hypertension.   While some patients with pulmonary hypertension may be born with the SS genotype, Dr. Voelkel’s team at University of Colorado has demonstrated that it is also possible for a somatic genetic mutation to lead to a monoclonal expansion of a dysfunctional phenotype.  A characteristic of this dysfunctional phenotype may, in fact, be diminished PGIS promotion activity due to diminished repeat sequences in the PGIS gene.